Abstract
The Wnt/β-catenin pathway is a well-known oncogenic pathway. Its suppression has long been considered as an important challenge in treating cancer patients. Among colon cancer patients in particular, most patients carry an adenomatous polyposis coli (APC) mutation that leads to an aberration of Wnt/β-catenin pathway. To discover the small molecule inhibitors of the Wnt/β-catenin pathway, we conducted high-throughput screening in APC-mutant colon cancer DLD-1 cells using a transcriptional reporter assay, which identified a selective Wnt/β-catenin pathway inhibitor, K-756. K-756 stabilizes Axin and reduces active β-catenin, and inhibits the genes downstream of endogenous Wnt/β-catenin. We subsequently identified that K-756 is a tankyrase (TNKS) inhibitor. TNKS, which belongs to the PARP family, poly-ADP ribosylates Axin and promotes Axin degradation via the proteasome pathway. K-756 binds to the induced pocket of TNKS and inhibits its enzyme activity. Moreover, PARP family enzyme assays showed that K-756 is a selective TNKS inhibitor. K-756 inhibited the cell growth of APC-mutant colorectal cancer COLO 320DM and SW403 cells by inhibiting the Wnt/β-catenin pathway. An in vivo study showed that the oral administration of K-756 inhibited the Wnt/β-catenin pathway in colon cancer xenografts in mice. To further explore the therapeutic potential of K-756, we also evaluated the effects of K-756 in non-small cell lung cancer cells. Although a single treatment of K-756 did not induce antiproliferative activity, when K-756 was combined with an EGFR inhibitor (gefitinib), it showed a strong synergistic effect. Therefore, K-756, a novel selective TNKS inhibitor, could be a leading compound in the development of anticancer agents. Mol Cancer Ther; 15(7); 1525-34. ©2016 AACR.
Highlights
The Wnt/b-catenin pathway controls many biologic processes, including cell proliferation, stem cell renewal, and tissue development [1]
When the Wnt ligand–mediated signaling is absent, b-catenin is degraded by a destruction complex, which is formed by adenomatous polyposis coli (APC), glycogen synthase kinase 3b (GSK3b), casein kinase (CK) 1a, and Axin [11]
We identified K-756 as a Wnt/b-catenin pathway small molecule inhibitor from high-throughput screening using a Wnt/ b-catenin reporter assay in APC-mutant DLD-1 colon cancer cells
Summary
The Wnt/b-catenin pathway controls many biologic processes, including cell proliferation, stem cell renewal, and tissue development [1]. When Wnt ligands bind to Frizzled (Frzd) receptors, a key downstream factor, b-catenin, localizes to the nucleus and forms a transcription complex with T-cell factor The b-catenin/TCF complex switches on the downstream genes such as MYC, BIRC5 (SURVIVIN), FGF20, ASCL2, CEMIP (KIAA1199), VEGFA, DHRS9, CCND1, TNNC1, and AXIN2 [3,4,5,6,7,8,9,10]. The hyperactivation of the Wnt/b-catenin pathway is observed in many cancers including colon, gastric, and hepatocellular. 1R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan. When the Wnt ligand–mediated signaling is absent, b-catenin is degraded by a destruction complex, which is formed by adenomatous polyposis coli (APC), glycogen synthase kinase 3b (GSK3b), casein kinase (CK) 1a, and Axin [11].
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